Cardiac hypertrophy occurs in response to mechanical or hormonal stimuli and is often found in association with the disease process of hypertension. In hypertension, the development of even mild cardiac hypertrophy increases the risk of arrhythmias and death. The renin-angiotensin system (RAS) participates in the pathophysiology of many forms of hypertension, evidenced by the decrease in blood pressure and prevention or regression cardiac hypertrophy seen in hypertensive patients treated with angiotensin II converting enzyme (ACE) inhibitors. The RAS could mediate cardiac hypertrophy indirectly by increasing peripheral vascular resistance or directly by stimulating protein synthesis and growth of heart cells. We have characterized the angiotensin II cardiac receptor demonstrating that it is saturable, reversible, specific, and modulated by divalent cations and guanine nucleotides. We have also shown that angiotensin II cardiac receptors couple to voltage-sensitive calcium channels and to phospholipase C, the latter resulting in increased amounts of water soluble inositol phosphates and increased activity of protein kinase C. Our preliminary data indicate that angiotensin II is a potent stimulus of protein synthesis and cell growth in cultured embryonic heart cells. These data suggest that circulating or locally-produced angiotensin II may be capable of stimulating cardiac hypertrophy. We have also shown that pressure overload cardiac hypertrophy in adult rats is fully prevented by pretreatment with an ACE inhibitor. This indicates that angiotensin II may have a direct modulatory role in cardiac growth in adult animals, independent of afterload. Our goals are to determine the role of the RAS in stimulating cardiac hypertrophy in rat heart and whether an intracardiac RAS contributes to this process. We will establish whether angiotensin peptides directly stimulate protein and RNA synthesis (and cell growth) in cultures of rat cardiomyocytes. The receptor will be characterized pharmacologically and the time and dose dependency of the responses determined. The distribution of angiotensinogen, renin, and angiotensin II converting enzyme mRNA will be determined in rat heart by in situ hybridization and the translatable products angiotensinogen, renin, and angiotensin II, co-localized by EM-immunocytochemistry. The contribution of an intracardiac RAS in cardiac hypertrophy will be probed by determining whether angiotensinogen, renin, and angiotensin II converting enzyme mRNA are regulated in experimental and genetic forms of high, normal, and low renin hypertension, using dot-blot and Northern hybridization analysis. The research will establish the importance of angiotensin peptides in modulating cardiac hypertrophy and define the relative roles of the circulating and/or intracardiac RAS, including the mechanisms regulating these systems. The hypotheses to be tested will more broadly define hormonally-mediated mechanisms of cardiac hypertrophy and will be relevant in the treatment of diseases such as hypertension.